Skip to main content

Advertisement

SpringerLink
Log in

Amyloid-β disrupts ongoing spontaneous activity in sensory cortex

  • Original Article
  • Published:
Brain Structure and Function Aims and scope Submit manuscript

Abstract

The effect of Alzheimer’s disease pathology on activity of individual neocortical neurons in the intact neural network remains obscure. Ongoing spontaneous activity, which constitutes most of neocortical activity, is the background template on which further evoked-activity is superimposed. We compared in vivo intracellular recordings and local field potentials (LFP) of ongoing activity in the barrel cortex of APP/PS1 transgenic mice and age-matched littermate Controls, following significant amyloid-β (Aβ) accumulation and aggregation. We found that membrane potential dynamics of neurons in Aβ-burdened cortex significantly differed from those of nontransgenic Controls: durations of the depolarized state were considerably shorter, and transitions to that state frequently failed. The spiking properties of APP/PS1 neurons showed alterations from those of Controls: both firing patterns and spike shape were changed in the APP/PS1 group. At the population level, LFP recordings indicated reduced coherence within neuronal assemblies of APP/PS1 mice. In addition to the physiological effects, we show that morphology of neurites within the barrel cortex of the APP/PS1 model is altered compared to Controls. These results are consistent with a process where the effect of Aβ on spontaneous activity of individual neurons amplifies into a network effect, reducing network integrity and leading to a wide cortical dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abeles M, Prut Y, Bergman H, Vaadia E (1994) Synchronization in neuronal transmission and its importance for information processing. Prog Brain Res 102:395–404

    Article  CAS  PubMed  Google Scholar 

  • Ahissar E, Haidarliu S, Zacksenhouse M (1997) Decoding temporally encoded sensory input by cortical oscillations and thalamic phase comparators. Proc Natl Acad Sci USA 94:11633–11638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arieli A, Shoham D, Hildesheim R, Grinvald A (1995) Coherent spatiotemporal patterns of ongoing activity revealed by real-time optical imaging coupled with single-unit recording in the cat visual cortex. J Neurophysiol 73:2072–2093

    CAS  PubMed  Google Scholar 

  • Azouz R, Gray CM (2000) Dynamic spike threshold reveals a mechanism for synaptic coincidence detection in cortical neurons in vivo. Proc Natl Acad Sci USA 97:8110–8115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beker S, Kellner V, Kerti L, Stern EA (2012) Interaction between amyloid-beta pathology and cortical functional columnar organization. J Neurosci 32:11241–11249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM (2011) Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat Neurosci 14:750–756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bero AW, Bauer AQ, Stewart FR, White BR, Cirrito JR, Raichle ME, Culver JP, Holtzman DM (2012) Bidirectional relationship between functional connectivity and amyloid-beta deposition in mouse brain. J Neurosci 32:4334–4340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, Staufenbiel M, Konnerth A, Garaschuk O (2008) Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321:1686–1689

    Article  CAS  PubMed  Google Scholar 

  • Cao L, Schrank BR, Rodriguez S, Benz EG, Moulia TW, Rickenbacher GT, Gomez AC, Levites Y, Edwards SR, Golde TE, Hyman BT, Barnea G, Albers MW (2012) Abeta alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo. Nat Commun 3:1009

    Article  PubMed  PubMed Central  Google Scholar 

  • Chorev E, Yarom Y, Lampl I (2007) Rhythmic episodes of subthreshold membrane potential oscillations in the rat inferior olive nuclei in vivo. J Neurosci 27:5043–5052

    Article  CAS  PubMed  Google Scholar 

  • Cowan RL, Wilson CJ (1994) Spontaneous firing patterns and axonal projections of single corticostriatal neurons in the rat medial agranular cortex. J Neurophysiol 71:17–32

    CAS  PubMed  Google Scholar 

  • D’Amore JD, Kajdasz ST, McLellan ME, Bacskai BJ, Stern EA, Hyman BT (2003) In vivo multiphoton imaging of a transgenic mouse model of Alzheimer disease reveals marked thioflavine-S-associated alterations in neurite trajectories. J Neuropathol Exp Neurol 62:137–145

    Article  PubMed  Google Scholar 

  • Denker M, Roux S, Linden H, Diesmann M, Riehle A, Grun S (2011) The local field potential reflects surplus spike synchrony. Cereb Cortex 21:2681–2695

    Article  PubMed  PubMed Central  Google Scholar 

  • Deschenes M, Timofeeva E, Lavallee P (2003) The relay of high-frequency sensory signals in the Whisker-to-barreloid pathway. J Neurosci 23:6778–6787

    CAS  PubMed  Google Scholar 

  • Destexhe A, Pare D (1999) Impact of network activity on the integrative properties of neocortical pyramidal neurons in vivo. J Neurophysiol 81:1531–1547

    CAS  PubMed  Google Scholar 

  • Devanand DP, Michaels-Marston KS, Liu X, Pelton GH, Padilla M, Marder K, Bell K, Stern Y, Mayeux R (2000) Olfactory deficits in patients with mild cognitive impairment predict Alzheimer’s disease at follow-up. Am J Psychiatry 157:1399–1405

    Article  CAS  PubMed  Google Scholar 

  • Grienberger C, Rochefort NL, Adelsberger H, Henning HA, Hill DN, Reichwald J, Staufenbiel M, Konnerth A (2012) Staged decline of neuronal function in vivo in an animal model of Alzheimer’s disease. Nat Commun 3:774

    Article  PubMed  PubMed Central  Google Scholar 

  • Gurevicius K, Lipponen A, Tanila H (2012) Increased cortical and thalamic excitability in freely moving APPswe/PS1dE9 mice modeling epileptic activity associated with Alzheimer’s disease. Cereb Cortex 23:1148–1158

    Article  PubMed  Google Scholar 

  • Haider B, McCormick DA (2009) Rapid neocortical dynamics: cellular and network mechanisms. Neuron 62:171–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  CAS  PubMed  Google Scholar 

  • Holt GR, Softky WS, Koch C, Douglas RJ (1996) Comparison of discharge variability in vitro and in vivo in cat visual cortex neurons. J Neurophysiol 75(5):1806–1814

    CAS  PubMed  Google Scholar 

  • Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159–170

    Article  CAS  PubMed  Google Scholar 

  • Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37:925–937

    Article  CAS  PubMed  Google Scholar 

  • Kellner V, Menkes-Caspi N, Beker S, Stern EA (2014) Amyloid-β alters ongoing neuronal activity and excitability in the frontal cortex. Neurobiol Aging 35:1982–1991

    Article  CAS  PubMed  Google Scholar 

  • Knowles RB, Gomez-Isla T, Hyman BT (1998) Abeta associated neuropil changes: correlation with neuronal loss and dementia. J Neuropathol Exp Neurol 57:1122–1130

    Article  CAS  PubMed  Google Scholar 

  • Knowles RB, Wyart C, Buldyrev SV, Cruz L, Urbanc B, Hasselmo ME, Stanley HE, Hyman BT (1999) Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer’s disease. Proc Natl Acad Sci USA 96:5274–5279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lampl I, Reichova I, Ferster D (1999) Synchronous membrane potential fluctuations in neurons of the cat visual cortex. Neuron 22:361–374

    Article  CAS  PubMed  Google Scholar 

  • Le R, Cruz L, Urbanc B, Knowles RB, Hsiao-Ashe K, Duff K, Irizarry MC, Stanley HE, Hyman BT (2001) Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer disease: implications for neural system disruption. J Neuropathol Exp Neurol 60:753–758

    Article  CAS  PubMed  Google Scholar 

  • Leger JF, Stern EA, Aertsen A, Heck D (2005) Synaptic integration in rat frontal cortex shaped by network activity. J Neurophysiol 93:281–293

    Article  PubMed  Google Scholar 

  • Mitzdorf U (1991) Physiological sources of evoked potentials. Electroencephalogr Clin Neurophysiol Suppl 42:47–57

    CAS  PubMed  Google Scholar 

  • Mitzdorf U (1994) Properties of cortical generators of event-related potentials. Pharmacopsychiatry 27:49–51

    Article  CAS  PubMed  Google Scholar 

  • Nauhaus I, Busse L, Carandini M, Ringach DL (2009) Stimulus contrast modulates functional connectivity in visual cortex. Nat Neurosci 12:70–76

  • Okun M, Naim A, Lampl I (2010) The subthreshold relation between cortical local field potential and neuronal firing unveiled by intracellular recordings in awake rats. J Neurosci 30:4440–4448

    Article  CAS  PubMed  Google Scholar 

  • Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L (2007) Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55:697–711

    Article  CAS  PubMed  Google Scholar 

  • Petersen CCH, Grinvald A, Sakmann B (2003a) Spatiotemporal dynamics of sensory responses in layer 2/3 of rat barrel cortex measured in vivo by voltage-sensitive dye imaging combined with whole-cell voltage recordings and anatomical reconstructions. J Neurosci 23:1298–1309

  • Petersen CCH, Hahn TTG, Mehta M, Grinvald A, Sakmann B (2003b) Interaction of sensory responses with spontaneous depolarization in layer 2/3 barrel cortex. Proc Natl Acad Sci USA 100:13638–13643

  • Saleem AB, Chadderton P, Apergis-Schoute J, Harris KD, Schultz SR (2010) Methods for predicting cortical UP and DOWN states from the phase of deep layer local field potentials. J Comput Neurosci 29:49–62

    Article  PubMed  PubMed Central  Google Scholar 

  • Salinas E, Sejnowski TJ (2001) Correlated neuronal activity and the flow of neural information. Nat Rev Neurosci 2:539–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanchez-Vives MV, Mattia M, Compte A, Perez-Zabalza M, Winograd M, Descalzo VF, Reig R (2010) Inhibitory modulation of cortical up states. J Neurophysiol 104:1314–1324

    Article  PubMed  Google Scholar 

  • Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT (2005) Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci 25:7278–7287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spires-Jones TL, Meyer-Luehmann M, Osetek JD, Jones PB, Stern EA, Bacskai BJ, Hyman BT (2007) Impaired spine stability underlies plaque-related spine loss in an Alzheimer’s disease mouse model. Am J Pathol 171:1304–1311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steriade M, Nunez A, Amzica F (1993) A novel slow (<1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components. J Neurosci 13:3252–3265

    CAS  PubMed  Google Scholar 

  • Stern EA, Kincaid AE, Wilson CJ (1997) Spontaneous subthreshold membrane potential fluctuations and action potential variability of rat corticostriatal and striatal neurons in vivo. J Neurophysiol 77:1697–1715

    CAS  PubMed  Google Scholar 

  • Stern EA, Jaeger D, Wilson CJ (1998) Membrane potential synchrony of simultaneously recorded striatal spiny neurons in vivo. Nature 394:475–478

    Article  CAS  PubMed  Google Scholar 

  • Stern EA, Bacskai BJ, Hickey GA, Attenello FJ, Lombardo JA, Hyman BT (2004) Cortical synaptic integration in vivo is disrupted by amyloid-beta plaques. J Neurosci 24:4535–4540

    Article  CAS  PubMed  Google Scholar 

  • Trick GL, Silverman SE (1991) Visual sensitivity to motion: age-related changes and deficits in senile dementia of the Alzheimer type. Neurology 41:1437–1440

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Institute on Aging at the National Institute on Health (Grant Number AG024238); the Legacy Heritage Bio-Medical Program of the Israel Science Foundation (Grant Number 688/10); and Marie Curie European Reintegration Grant within the 7th European Community Framework Programme (Grant Number PERG03-GA-2008-230981). We thank Profs. Israel Nelken and Moshe Abeles for their helpful suggestions on this manuscript.

Author information

Authors and Affiliations

  1. Gonda Brain Research Center, Bar-Ilan University, 52900, Ramat Gan, Israel

    Shlomit Beker, Miri Goldin, Noa Menkes-Caspi, Vered Kellner, Gal Chechik & Edward A. Stern

  2. Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA

    Edward A. Stern

Authors
  1. Shlomit Beker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miri Goldin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noa Menkes-Caspi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vered Kellner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gal Chechik
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Edward A. Stern
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward A. Stern.

Appendix

Appendix

See Tables 1, 2, 3 and Figs. 6, 7.

Table 1 Distribution of ages of animals for all experiments
Full size table
Table 2 Membrane potential properties of Control and APP/PS1 mice (in mV)
Full size table
Table 3 Median and MAD of spike shape properties
Full size table
Fig. 6
figure 6

Example of all-points voltage histogram recorded from a Control barrel cortex neuron. The histogram was segmented to Up and Down states using Gaussian mixture models. Colored vertical bars indicate means and transitions of the states. Transitions were calculated at ¼ and ¾ of the difference between the means

Full size image
Fig. 7
figure 7

Examples of CV2 values of LFP troughs timing for Controls (a–d) and APP/PS1 (e–h). Two main characteristics are observed. First: a downward shift of the cloud of CV2 values among the Controls, creating mean of values that is farther from the upper bound in the Control group, than the APP/PS1 (black line in the examples). Second, the spread of values is more even along the Y axis among the APP/PS1. These characteristics imply more perturbed, variable recordings of APP/PS1 (Holt et al. 1996)

Full size image

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Beker, S., Goldin, M., Menkes-Caspi, N. et al. Amyloid-β disrupts ongoing spontaneous activity in sensory cortex. Brain Struct Funct 221, 1173–1188 (2016). https://doi.org/10.1007/s00429-014-0963-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00429-014-0963-x

Keywords

Search

Navigation